2,4,6-Tribromoanisole and 2,4,6-Trichloroanisole

Odorous taints, although relatively common in the food and beverage industries, are extremely rare in the pharmaceutical and consumer healthcare industries. Since 2009, multiple pharmaceutical and consumer healthcare companies have recalled products for a musty moldy odorous taint, imparted by 2,4,6-tribromoanisole (TBA), and detected through customer complaints. These taints arise from an external source as opposed to off-odors or off-flavors, which can arise from internal changes to a product from microbial spoilage. The haloanisole taints, TBA and 2,4,6-tricholoroanisole (TCA), generated by the fungal biomethylation of 2,4,6-tribromophenol (TBP) and 2,4,6-trichlorophenol (TCP) respectively, have very low thresholds for detection by the human nose, at parts per trillion (ppt), and high volatility relative to other organohalogen taints.

NICHOLAS RIGG/GETTY IMAGES

In the fall of 2010, the Parenteral Drug Association (PDA) established a task force of industry representatives with expertise in quality assurance, packaging, supply chain, microbiology, analytical chemistry, and toxicology. The Technical Report written by this task force benchmarks the current situation regarding TBA, TCA, TBP, and TCP taints and odors in the industry, addresses supply chain and analytical risk-mitigation strategy, and provides toxicology and safety data as well as highlights concerns from regulatory authorities. The purpose of this article is to summarize the findings of the PDA Technical Report No. 55 on this topic, published in April 2012 (1).

Background

Wood pallets—an unexpected source. Almost all of the recalls cited in this report have been linked to TBA taints entering into Puerto Rico facilities from wood products that have been treated with TBP. Although TBP is registered as a wood preservative in South America, it is not registered in the United States. Thus, the risk of TBP entering the supply chain via wood pallets is higher for manufacturing sites based in Puerto Rico than in the continental United States. In addition, the warm, humid environment in Puerto Rico increases the probability that xerophilic fungi will grow on wood pallets converting TBP to TBA through biomethylation.

Prior to the series of TBA incidents in 2009, pallets were considered to have a very low risk within the supply chain, and as such, had limited quality oversight. A typical Quality Assurance (QA) manager, therefore, would have little or no knowledge about the standards or lifecycles of pallets. Some information on the pallet industry and types of pallets is included in the PDA Technical Report.

Multiple companies affected. Starting in December 2009, multiple companies identified issues related to TBA taints. As of August 2012, there have been 20 recalls from eight pharmaceutical and consumer healthcare companies that share many common features (see Table I). Details from these recalls are provided in the PDA Technical Report. Some commonalities among the cases include: TBP-treated lumber was used for wood pallets; the geographical location of plastic packaging components manufactured was Puerto Rico; climatic conditions where plastic packaging components were manufactured and stored were conducive to fungal growth; tainting of plastic packaging components occurred; and the implicated products were largely compressed tablets.

The initial investigations of musty, moldy odors by Johnson and Johnson McNeil Consumer Healthcare inconclusively focused on fungal growth on the tablets because of the complaints of a moldy odor (1). Subsequent analysis by gas chromatography (GC)/mass spectrometry (MS)/olfactometry indicated that the odor was due to the taint TBA. It was concluded that the most probable root cause of the odor from TBA was exposure of the product to packaging components that had been shipped to and stored at the pharmaceutical manufacturing site on wood pallets constructed from TBP-treated lumber that had entered the supply chain. It was observed that the odor persisted in the open containers after tablets had been removed, thereby suggesting that TBA resided in high density polyethylene (HDPE) containers and/or cap liners (1). In March 2010, FDA, in response to these recalls, developed a Level 2 GMP Building and Facility Q&A guidance to address the use of pallets to prevent risks from TBA taints (4).

These cases reinforce that pharmaceutical and consumer products are susceptible to contamination from haloanisole taints, such as TBA and TCA. Thus, the intent of the PDA Technical Report is to provide more guidance for the bio/pharmaceutical industry on how to identify and mitigate risks from TBA or TCA tainting.